Targeting Centrosome Clustering as a Novel Therapy for Autosomal Dominant Polycystic Kidney Disease
Abstract
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is considered one of the most common life-threatening inherited genetic diseases. The incidence of ADPKD in the population is high, affecting up to 1 in 400 births across all racial and ethnic groups, impacting ~13 million individuals worldwide. ADPKD is a significant cause of kidney failure, accounting for ~5% of patients with End-Stage Renal Disease (ESRD) requiring renal transplant and dialysis, at an annual cost of more than $1.5 billion in the United States alone. Almost half of the patients develop kidney failure by the fifth or sixth decades of life, in conjunction with extrarenal manifestations such as hypertension, abdominal pain, and polycystic liver disease. Management of ADPKD is disproportionately costly, as approximately 6%-10% of all individuals receiving dialysis and renal transplant in the United States are afflicted with ADPKD. Yet, the current state of therapy for ADPKD is dismal. Despite multiple attempts with trials of targeted therapeutics, none has been an unmitigated success in the clinic. The only therapeutic approved in the United States, Tolvaptan, reduces the rate of decline in renal function by a mere 2%-3% annually. Moreover, there remain concerns regarding liver toxicity and increased urine volume, which can result in considerable interference with the quality of life. Thus, the nephrology community is left with renal dialysis and transplantation as the only viable options. None of these treatments are satisfactory for such a common disease in the 21st century, and new therapeutic directions are desperately needed. ADPKD is characterized by dysregulation of epithelial cell physiology, cytoskeletal morphology, and hyperproliferation of normally quiescent tubular cells, which profoundly alters the organ architecture and impairs renal function. It is now established that ADPKD is a “ciliopathy,” or a disease caused by ciliary dysfunction. Cilia are microtubule-based structures that play important chemo- and mechanosensory roles in cells. In the kidney, cilia are found on renal progenitor cells during embryonic development and epithelial cells lining the various segments of mature nephrons. The cilia protrude from the apical surface and are in contact with the extracellular environment, acting as a cellular sensor that regulates epithelial cell growth, homeostasis, and repair. The assembly of cilia is templated by the centrosome, the major microtubule-organizing center in mammalian cells. Most cells in the human body, including the kidney, contain a solitary centrosome and cilium, and cells have evolved tight regulatory mechanisms to ensure each cell contains only one of each organelle. Using ADPKD human and mouse experimental data, we recently discovered that abnormal biogenesis of centrosomes, resulting in an increase in their number in tubular cells, plays a crucial role in cyst development and growth. Essentially, these cells behave as “bad actors” that impact not only their progeny during cell proliferation, but also non-dividing neighboring tubular cells to drive cyst formation. Based on these findings, we hypothesize that targeting and eliminating these cells will reduce cystogenesis and improve renal function in ADPKD patients. We have now generated strong preliminary evidence demonstrating that cystic cells with ectopic centrosomes, the cells whose proliferation leads to ADPKD, can be selectively killed when treated with novel compounds that specifically target cells with abnormal centrosomes. The elimination of these cells results in improvements in kidney morphology and function, highlighting the feasibility of this approach. This grant proposal focuses on the preclinical evaluation of two such small molecule inhibitors, CCB02 and PJ34, in blocking cyst initiation and growth in ADPKD mice and cultured cells. First, we propose to test these inhibitors using slow- and rapid onset mouse models of ADPKD. Next, we
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010198
Entities
People
- Mohamed Mahjoub
Organizations
- United States Army
- Washington University in St. Louis